Protein kinase C epsilon as modulator of anxiety, alcohol consumption and self-administration of drugs of abuse

Abstract

The present invention is directed to the production of PKC isozyme ε (PKCε)-deficient cells and non-human animals. The present invention is further directed to the identification of PKCε as a target for drugs that reduce anxiety. According to the present invention, PKCε-inhibiting compounds act in synergy with drugs acting at the GABA A receptor. The present invention is also directed to the use of modulators of PKCε to modulate alcohol consumption, self-administration of other drugs of abuse, and the effects of alcohol consumption as well as the use of inhibitors of PKCε, either alone or in conjunction with allosteric agonists of GABA A receptors, to treat conditions, such as addiction, withdrawal syndrome, skeletal muscle spasms, convulsive seizures, and epilepsy, that are amenable to treatment by allosteric agonists of GABA A receptors. Additional aspects of the present invention are diagnostic methods for identifying individuals at risk for becoming alcoholics or abusers of other drugs and kits for performing such diagnostic methods. The present invention relates to: cells and non-human animals deficient for the PKC isozyme ε (PKCε); the use of PKCε as a target for drugs; the use of inhibitors of PKCε in methods of reducing anxiety and treating conditions associated with insufficient activity of the GABA A receptor; the use of modulators of PKCε in methods of modulating alcohol consumption, modulating self-administration of other drugs of abuse, and altering the effects of alcohol; pharmaceutical compositions comprising inhibitors of PKCε and allosteric agonists of GABA A receptors; and the identification of individuals with enhanced susceptibility to alcoholism or other forms of addiction.

1. A composition comprising a selective inhibitor of PKCε, wherein said selective inhibitor is a fragment of PKCε and an agonist of a GABA A  receptor, wherein said agonist is a benzodiazepine or barbiturate. 
     
     
       2. The composition of  claim 1 , wherein the selective inhibitor of PKCε is selected from the group consisting of εV1-1, εV1-2, εV1-3, εV1-4, εV1-5, εV1-6 and εV1-7. 
     
     
       3. The composition of  claim 1 , wherein the beuzodiazepine is selected from the group consisting of: alprazolam, chlordiazepoxide, chlordiazepoxide hydrochloride, chlormezanone, clobazam, clonazepam, clorazepate dipotassium, diazepam, droperidol, estazolam, fentanyl citrate, flurazepam hydrochloride, halazepam, lorazepam, midazolam hydrochloride, oxazepam, prazepam, quazepam, temazepam, and triazolam. 
     
     
       4. The composition of  claim 1 , wherein the barbiturate is selected from the group consisting of: amobarbital, amobarbital sodium, aprobarbital, butabarbital sodium, hexobarbital sodium, mephobarbital, metharbital, methohexital sodium, pentobarbital, pentobarbital sodium, phenobarbital, phenobarbital sodium, secobarbital, secobarbital sodium, talbutal, thiamylal sodium, and thiopental sodium.